Gov't Study Tying Ginkgo to Cancer Challenged

WASHINGTONA rat study reported by the National Toxicology Program (NTP), a division of the Department of Human Services, linked Ginkgo biloba administered to rats and mice to increased development of cancer in the thyroid, liver and nose, but experts, including several on the NTP peer-review panel, questioned the validity of the Ginkgo extract used and emphasized the rat study results was not intended to evaluate risk in humans.

The watchdog group Center for Science in the Public Interest (CPSI) downgraded its safety rating for Ginkgo and advised the public not to consume Ginkgo biloba in supplements, teas, energy drinks or any other product. "Ginkgo has been used in recent years to let companies pretend that supplements or energy drinks or supplements with it confer some sort of benefit for memory or concentration," said Michael Jacobson, executive director of CSPI.  The evidence for those claims has been dubious, at best.  The pretend benefits are now outweighed by the real risk of harm."

However, in the text of the study report from NTP, Paul Howard, PH.D., director of the Office of Scientific Coordination at FDA, advised the review panel "is specifically not to enter into any risk assessment related to humans." He said these reports were not intended to evaluate risk for humans.

Steven Dentali, PH.D., chief science officer for the American Herbal Products Association (AHPA), also reviewed the study and contributed comments to the panel, specifically noting the Ginkgo extract used in the study was not representative of the Ginkgo extracts marketed and sold in the United States. Considering the lack in similarity between the study extract and those common in the United States, Dentali warned it is incorrect to represent this extract as similar to those used by American consumers. He further noted t he supplier of the extract used in the study intended to make a unique formulation for drug development, and the extract contains "highly concentrated effective content," according to the supplier.

Dentali offered the panel some data comparing the test extract to published analyses of commonly consumed extract and to recognized standards. He recommended the data be highlighted in the report  and the title changed to reflect the extract as "specific."

"I'm disappointed that NTP did not adopt AHPA's recommendations to properly qualify the extract that was studied and its relevance to consumers and the marketplace," Dentali said. "This is in spite of the fact that two of NTP's own peer reviewers agreed with my suggestion to include the data table showing the constituent ratios of the NTP unique test material versus readily available consumer ginkgo products. The assertions and conclusions in the final NTP report are not necessarily relevant to other commercially available ginkgo products."

Ashley Roberts, Ph.D., Senior VP of the Food & Nutrition Group at Intertek Cantox, took issue with several aspects of the study and conclusions, including the stability of the dosing formulation. He also noted the results were not unusual, as the rat population used is known to have spontaneous development of liver tumors. In his opinion, the NTP should have established a no-observed-adverse-effect level for risk assessment purposes.

The conclusion proposed by the NTP study report was for "some evidence" of carcinogenic activity from Ginkgo in male rats and "clear evidence" of carcinogenic activity of Ginkgo in female mice.

Roberts suggested the NTP downgrade its conclusion from "some evidence" to "equivocal evidence" relative to the thyroid tumors, noting the liver tumors in mice and thyroid tumors in rats may have little relevance to humans, w ho commonly consume much lower levels of Ginkgo than what was used the study.

However, despite the cautions and challenges, CSPI touted the "clear" and "some" evidence conclusions in its warning to the public against Ginkgo consumption.

The herbal industry was quick to stress it had expressed concerns to NTP over the material used, criticisms adopted by peer panel reviewers Russell Cattley, Ph.D., VMD, of Auburn University, and Jon Mirsalis, Ph.D., SRI International and principal reviewer.

The American Botanical Council (ABC) sent public comments to NTP, suggesting the authors consider revising the draft report to address several issues.  According to ABC, the Chinese ginkgo extract manufactured in Shanghai "is not consistent with any compendial botanical and chemical standards for quality as set forth in various official pharmacopeias and does not conform to the well-established chemical profiles, quality, and purity of the leading, clinically tested ginkgo extracts produced by the pioneering Willmar Schwabe Pharmaceuticals of Karlsruhe, Germany, and Indena SpA in Milan, Italy."

Further, ABC expressed concerns the dosage levels administered in the study were 55- to 108-times higher than what is normally ingested by consumers.

"The NTPs public message, and the resulting media reports, totally miss this point about the actual identity of the ginkgo extract and the high-dosage levels, and will probably cause confusion among consumers and health professionals alike," said Mark Blumenthal, founder and executive director of ABC. "At best, what NTP can say is that significantly high doses of this particular Shanghai Chinese ginkgo extractwhen added to a corn-oil baseproduced cancer in the lab animals."

Bill J. Gurley, PhD, professor of pharmaceutical sciences in the College of Pharmacy at the University of Arkansas School for Medical Sciences, Little Rock, and co-author of ABC's comment letter to NTP, said, Almost anything will create cancer in rats and mice when its fed to them at high doses for two years. All toxicologists and pharmacologists are aware of the susceptibility of certain strains of rodents used for research purposes to develop various forms of cancer and other diseases when subjected to various substances."

The other co-author of ABC comments, Rick Kingston, PharmD, president of regulatory and scientific affairs at SafetyCall Internationaland professor of pharmacy at the University of Minnesota College of Pharmacy, called the report disappointing. Notwithstanding major design flaws in the study in identifying an appropriate compound to represent available ginkgo in the market," he said.  "Even the reviewers voiced adamant proclamations that the results in this animal research were not intended for direct extrapolation to humans. For this oversight to not be reconciled by the NTP review group is disconcerting, especially since misinterpretation of the results by well-intentioned, but scientifically unsophisticated media outlets, and possibly even consumer groups, should have been an expected outcome."

Visit the AHPA website to find AHPA's analysis of the extract used in the NTP studies and AHPA's comments to NTP (including the data table created by Dentali).

ABC's comments to NTP are published on the NPT website.